Hyperglycemia and insulin resistance are common in critically ill patients, even when glucose homeostasis has previously been normal. Increased gluconeogenesis, despite abundantly released insulin, is probably central to this disruption of glucoregulation (Wolfe R R, et al Metabolism 1979; 28: 210-220 Wolfe R R, et al. N Engl J Med. 1987; 317; 403-408).
Hence, the liver appears a major site of insulin resistance. Reduced insulin-stimulated glucose uptake also exists in skeletal muscle and heart (Wolfe R R, et al Metabolism 1979; 28: 210-220, Shangraw R E, et al. Metabolism 1989; 38: 983-9893). Overall glucose uptake, however, is increased but takes place mainly in insulin-independent tissues such as the brain, the red blood cells and in wounds. The increased glucose turnover and insulin-resistance of hyperglycemia were previously interpreted as a plea for tolerating moderately elevated (≦215 mg/dl) blood glucose levels during critical illness (Mizock B A. et al. Am J Med. 1995; 98:75-84; McCowen K C, et al. Crit Care Clin. 2001; 17: 107-124). More pronounced hyperglycemia in diabetic surgical patients has been associated with high incidence of postoperative infections (Fietsam R jr, et al. Am Surg. 1991; 57: 551-557) and after stroke and head injury with poor prognosis (O'Neill P A, Davies I, Scott J F, et al. Stroke 1999). In diabetic patients suffering from acute myocardial infarction, blood glucose control below 215 mg/dl has been shown to improve long-term outcome (Malmberg K, et al. Circulation. 1999; 99: 2626-2632; Malmberg K BMJ 1997; 314: 1512-1515; Malmberg K, et al. J Am Coll Cardiol. 1995; 26: 57-65). We recently hypothesized that even moderate hyperglycemia, between 110 mg/dl and 200 mg/dl, in diabetic as well as in non-diabetic critically ill patients is directly or indirectly harmful to vital organs and systems (Van den Berghe G, et al. N Engl J Med. 2001; 345: 1359-1367) hence contributing to adverse outcome. A prospective, randomized, controlled study performed in 1548 ICU patients confirmed this hypothesis by showing that strict glycemic control below 110 mg/dl with insulin infusion substantially reduces morbidity and mortality (Van den Berghe G, et al. N Engl J Med. 2001; 345: 1359-1367). Indeed, intensive insulin therapy reduced overall ICU mortality from 8% to 4.6%, and from 20.2% to 10.6% among patients requiring more than 5 days intensive care. Intensive insulin therapy also halved the incidence of blood stream infections, prolonged inflammation, acute renal failure requiring dialysis or hemofiltration, critical illness polyneuropathy and transfusion requirements. Patients receiving intensive insulin therapy were also less likely to require prolonged mechanical ventilation and intensive care. It remained an open question, however, whether the benefits are brought about directly by the infused insulin per se or by the prevention of hyperglycemia, as both occurred concomitantly.
Present findings clearly demonstrate that strict maintenance of normoglycemia with intensive insulin therapy reduces intensive care and hospital mortality and morbidity of critically ill adult patients in a surgical ICU. The findings of present study also reveal factors determining insulin doses needed to maintain normoglycemia as well as the impact of insulin dose versus blood glucose level on the observed outcome benefits have been established.
By a prospective, randomized, controlled trial in a single center in a 56-bed predominantly surgical ICU in a tertiary teaching hospital 1548 patients were randomly assigned to either strict normalization of blood glucose (80-110 mg/dl) with intensive insulin therapy from ICU admission onward or the conventional approach, in which insulin infusion is only initiated when blood glucose exceeds 215 mg/dL, to maintain blood glucose levels between 180 and 200 mg/dl. It was feasible and safe to achieve and maintain blood glucose levels below 110 mg/dL by using a simple insulin titration algorithm which takes on-admission patient- and disease-related factors such as BMI, history of diabetes, reason for ICU admission, severity of illness, on-admission hyperglycemia, as well as the caloric intake, time in ICU and concomitant medication (glucocorticoids) into account. Stepwise regression analysis indicated that, except for severity of illness and use of glucocorticoids, all these factors were independent determinants of mean insulin requirements, together explaining 36% of its variation. Nutritional intake was progressively increased from a mean 550 Cal on day 1 to a mean 1600 Cal from day 7 onward. The dose of insulin required to reach normoglycemia was highest and most variable during the first 6 hours after admission (a mean of 7 units per hour; 10% of the patients required more than 20 units per hour). Normoglycemia was reached within 24 h with, for a 70 kg patient, a mean 77 units per day on the first day and 94 units per day on day 7. Between day 7 and 12, caloric intake remained stable but insulin requirements decreased by 40%. Brief and clinically harmless hypoglycemia occurred in 5.2% of intensive insulin treated patients on the median 6th (IQR 2nd-14th) day versus in 0.8% of the conventionally treated patients on the 11th (2nd-10th) day. 
The observed benefits of intensive insulin therapy on morbidity and mortality were equally present whether or not patients received enteral feeding. The lowered blood glucose level rather than the insulin dose was related to the observed reduction in mortality (P<0.0001), critical illness polyneuropathy (P<0.0001), bacteremia (P=0.02) and inflammation (P=0.0006) but not to the prevention of acute renal failure, for which the insulin dose was an independent determinant (P=0.03). Among long-stay patients, maintaining strict normoglycemia appeared important for optimal risk reduction as intermediate (110-150 mg/dl) blood glucose levels were associated with a significantly higher incidence of most intensive care complications and death.
It has now demonstrated by that glycemia between 80 and 110 mg/dl (4.4 and 6.1 mmol/l), through a rigorous administration of insulin (intensive insulin therapy) can result in a spectacular reduction in mortality and morbidity. This major step forward in the treatment of critically ill patients, particularly since most large clinical trials on immunomodulatory treatment of sepsis and shock failed to demonstrate benefit.
However, intensive monitoring with fast and easy access of blood glucose may be a useful in order to accurately steer the delivery of insulin or insulin releasing factors. Malberg K. A., et al. 1994 (Diabetes Care 17: 1007-1014 (1994)), for instance, demonstrated that in a study of glucose control following myocardial infarction that infusion with insulin and glucose resulted in 18% of the patients developing hypoglycemia. A hypoglycemia defined as blood glucose below 0.3 mM/litre, is for instance known to increases risk of myocardial infarction and ventricular arrhythmia.
Moreover, Sakuri Y. et al. (Annals of surgery Vol. 222 No. 3 283-297 (1995)) demonstrated that burned patients have a negative balance between protein synthesis and breakdown, despite a nutritional intake and concluded that mechanism responsible for this imbalance was principally a high rate of protein breakdown. Sakuri Y. et al. Found that chronic insulin delivery 28 units/hour, could increase the protein breakdown. Although this striking finding that insulin infusion increases protein breakdown, in healthy volunteers as well in burned patients insulin delivery ameliorated the net catabolism of muscle protein. Sakuri K. A. et al concluded that for treatment of burned patient by insulin a lower dose would be preferable because of the potential problems of giving a caloric overload with high glucose dose insulin and because avoiding hypoglycemia such high dose treatment would be too clinical demanding. Moreover, Ferrando, -A-A; et al. (Ann-Surg. 1999 January; 229(1): 11-8) in an attempt to reverse the net muscle catabolism associated with severe burns, demonstrated that if large quantities of exogenous glucose required to maintain euglycemia, and hypoglycemia in patients with severe burns promoted skeletal muscle glucose uptake and net protein synthesis but was associated with caloric overload, suggesting an hidden hypoglycemia.
This demonstrates that intensive insulin treatment of critical ill patients for safety and efficacy of insulin and nutrient infusion therapy not only requires an intensive monitoring of blood glucose concentrations with easy and rapid access to blood glucose data and that a clear prediction per patient of the biological response to a given concentration of insulin van optimize the intensive insulin therapy of critical ill patients or subjects with insulin resistance or increased glucose uptake.
Present invention allows now to predict insulin requirement to maintain normoglycemia in an intensive care patient and to predict the impact of insulin dose versus blood glucose level on the observed outcome benefits.
Present inventions now reveals predictive factors that determine insulin doses needed to maintain normoglycemia as well as the impact of insulin dose versus glucose level on the observed outcome of benefit. Date of this invention the administration of insulin in intensive care patients can now be controlled by a titration protocol, the general guidelines for this protocol are given in the titration algorithm of this application. However, this protocol is still labor intensive.
However a second embodiment of present invention provides a control system that adapts the flow of the insulin infusion based on insulin requirement calculated by blood glucose levels and clinical parameters such as history of diabetes, Body Mass Index, blood glucose level on admission, reason of ICU admission, time in the ICU, type and severity of illness, caloric intake, obesity, drugs affecting insulin sensitivity. This automated insulin monitoring systems for intensive insulin therapy in patients in the ICU significantly reduces the workload and human resourse management problems and improves patient survivability.
This system can advise the medical team about the desired insulin administration rate or can apply a more automatic control. It has the following properties:    1. In the initial phase (first 24 h) the hyperglycemia is reduced, as quickly as possible, to stable normoglycemia without causing hypoglycemia.    2. The control system is robust (i.e., the blood glucose level is as stable as possible) against complicating factors (e.g., concomitant infection) and changing circumstances (e.g., decreasing insulin resistance, other route of feeding, change in medication, . . . ).